In 1997, the first documented instance of human influenza disease and death associated with a purely avian influenza virus (H5N1 strain) occurred in Hong Kong. Since 1997, highly virulent avian influenza viruses have continued to cause disease and even death in humans, as recently as March 2004. The basis for the unusual severity of illness with H5N1 influenza disease is unknown; however, cytokine deregulation was observed. The highly lethal H5N1 viruses are the only influenza virus strains that do not activate transforming growth factor-beta (TGF-beta). TGF-beta is arguably, the most potent immunosuppressive factor described to date. Our strong preliminary data indicated that neutralization of TGF-beta during influenza infection resulted in lethal disease and the viral neuraminidase protein (NA) was responsible for activating TGF-beta. These results suggested that TGF-beta induction might be a critical factor in influenza pathogenesis. Thus, the goal of these studies is to determine the regulation of TGF-beta by influenza virus NA. The specific aims are: 1. Determine the region of NA required for TGF-beta activation, and 2. Define the mechanism of TGF-beta activation by NA. These studies offer a unique opportunity to obtain information basic to understanding influenza pathogenesis and potentially lead to the development of new therapies.